Year: 2013
Type: article
Abstract: BACKGROUND: Airway hyperresponsiveness (AHR), a primary characteristic of asthma, involves increased airway smooth muscle contractility in response to certain exposures. We sought to determine whether common genetic variants were associated with AHR severity. METHODS: A genome-wide association study (GWAS) of AHR, quantified as the natural log of the dosage of methacholine causing a 20% drop in FEV1, was performed with 994 non-Hispanic white asthmatic subjects from three drug clinical trials: CAMP, CARE, and ACRN. Genotyping was performed on Affymetrix 6.0 arrays, and imputed data based on HapMap Phase 2, was used to measure the association of SNPs with AHR using a linear regression model. Replication of primary findings was attempted in 650 white subjects from DAG, and 3,354 white subjects from LHS. Evidence that the top SNPs were eQTL of their respective genes was sought using expression data available for 419 white CAMP subjects. RESULTS: The top primary GWAS associations were in rs848788 (P-value 7.2E-07) and rs6731443 (P-value 2.5E-06), located within the ITGB5 and AGFG1 genes, respectively. The AGFG1 result replicated at a nominally significant level in one independent population (LHS P-value 0.012), and the SNP had a nominally significant unadjusted P-value (0.0067) for being an eQTL of AGFG1. CONCLUSIONS: Based on current knowledge of ITGB5 and AGFG1, our results suggest that variants within these genes may be involved in modulating AHR. Future functional studies are required to confirm that our associations represent true biologically significant findings.
Source: BMC Medical Genetics
Authors: Blanca E Himes, Weiliang Qiu, Barbara Klanderman, John Ziniti, Jody Senter-Sylvia, Stanley J Szefler, Robert F Lemanske, Jr, Robert S Zeiger, Robert C Strunk, Fernando D Martinez, Homer Boushey, Vernon M Chinchilli, Elliot Israel, David Mauger, Gerard H Koppelman, Maartje AE Nieuwenhuis, Dirkje S Postma, Judith M Vonk, Nicholas Rafaels, Nadia N Hansel, Kathleen Barnes, Benjamin Raby, Kelan G Tantisira, Scott T Weiss
Institutions: Brigham and Women's Hospital, Boston Children's Hospital, Harvard University, National Jewish Health, University of Colorado Denver, University of Wisconsin–Madison, Kaiser Permanente, Washington University in St. Louis, University of Arizona, University of California, San Francisco, Pennsylvania State University, University Medical Center Groningen, University of Groningen, Beatrix Kinderziekenhuis, Johns Hopkins University
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,380
Awards: INTEGRATIVE GENOMICS APPROACHES TO MODEL THE GENETIC ARCHITECTURE OF ASTHMA, G1623277123, G162555452, G1700735027, Pharmacogenetics of Asthma Treatment, G1955273565, G2772107177, Integrative Genomics Approaches to Model the Genetic Architecture of Asthma, G291751459, G3893369592, CARE Network--St. Louis Center, G5329934708, G5541927788, G5638201504, G5831042680, G6413956449, Translational Genetics and Genomics of Airways Diseases, G6512022131, G7062379326, G7221295137, G7255980666, G7724463095, Genetics and Gene Expression Profiling in Asthma, Common Genetic Determinants of Asthma and COPD-PROGRAM PROJECT, G785151132, G794209665, G821063702, G8293452648, G8804100345, G9000000934, G9000023607, G9000056548, G9000111170, G9000273487, G9000301204, G9000319496, SYSTEMS APPROACHES TO THE EPIDEMIOLOGY, GENETICS AND GENOMICS OF LUNG DISEASES, EARLY INTERVENTION/CHRONIC OBSTRUCTIVE PULMONARY DISEASE
OpenAlex ID: W2136917709